Bioactive spermidine nanoparticles for effective cardiovascular recovery and diabetic therapy

• Calorie restrictive spermidine co-polymer was developed. • Spermidine-Lirag NPs regulate the glucose/lipid metabolism dysfunction. • Spermidine-Lirag NPs postpone the progression of myocardial fibrosis. • Spermidine-Lirag NPs hold potency for T2D and its cardiovascular complications. • Spermidine-Lirag NPs were prepared by homogeneous mixture of FNC technique. Cardiovascular complications account for more than 80% of type II diabetes (T2D)-related mortality every year. Although glucagon-like peptide 1 receptor agonists (GLP-1RA) can effectively maintain the glycemic level, their efficacy and related cardiovascular benefits are significantly limited owing to their short half-life. Hence, in this study, on the basis of calorie restriction theory, spermidine containing bioactive polymers have been developed to deliver liraglutide with sustained release kinetics. Calorie restrictive and cardiovascular beneficial spermidine (SPM) was conjugated to oxidized dextran to synthesize bioactive SPM-DEX polymer and the SPM-DEX/Liraglutide nanoparticles were successfully prepared using the flash nanocomplexation (FNC) technique via electrostatic polyelectrolyte complexation. Single administration of these sub-100 nm liraglutide nanoparticles efficiently prolonged the hypoglycemic efficacy of liraglutide for more than 4 days. Moreover, through modulating glucose metabolism dysfunction and excessive lipid metabolism, these long-acting liraglutide and SPM containing nanoparticles efficiently maintained a stable blood glucose level (BGL) and body weight in 30 days as biochemical indices, such as HbA1c and triglycerides, were all reduced to the normal range. In addition, by downregulating the Wnt/β-catenin signaling pathway, SPM containing nanoparticles effectively postponed the progression of myocardial fibrosis and systemically improved the systolic function of the cardiac left ventricle. We believe this highly biocompatible, bioactive and calorie restrictive spermidine-containing liraglutide nanoparticles with long-term hypoglycemic efficacy and cardiovascular benefits may hold great clinical potentials.